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Joseph Priestly discovered nitrous oxide in 1772, shortly after his discovery of oxygen. Humphry Davy was the first to identify the analgesic and anesthetic effects of nitrous oxide in the late eighteenth century. Oxygen was added to the nitrous oxide mixture in 1868 in order to prevent hypoxia that was commonly seen. The first detailed analysis of nitrous oxide-oxygen mixtures as they apply to pain relief without sedation or hypoxia was published by Stanislav Klikovich in 1881.


Nitrous oxide-oxygen mixtures were first applied in an ambulatory setting in 1955; dentists in Denmark used them for office-based procedures. A 50-50 mixture of nitrous oxide with oxygen (Entonox) has been used by the British Ambulance Service in a self-administered format since 1970.1 Nitrous oxide-oxygen mixtures became popular in the United States as a sedative/analgesic for use in the Emergency Department during the late 1970s.2


Nitrous oxide (N2O) is a colorless gas; it has a sweet odor and is heavier than air. The gas diffuses rapidly across biologic membranes, resulting in a rapid onset and short duration of action. The precise mechanism of action is unknown. However, involvement of the endogenous opioid system has been suggested.3The gas has the five actions of mild sedation, anxiolysis, mild to moderate analgesia, weak anesthesia, and mild dissociative effects.4


Nitrous oxide is 34 times more soluble in plasma than nitrogen. It quickly diffuses across biologic membranes (lung-blood and blood-CNS), which accounts for its rapid onset of action (60 to 90 seconds). The maximal effect occurs within 2 minutes of administration. Its duration of action is 2 to 5 minutes after discontinuation of the administration. Nitrous oxide does not have significant cardiovascular or respiratory depressant effects. It does not result in a loss of the patient’s protective airway reflexes. It rapidly depresses all cerebral cortical functions including all five senses. Nitrous oxide rapidly diffuses into pockets of trapped gas (dilated bowel, pneumothorax, pneumoperitoneum). Nitrogen is displaced and replaced by larger amounts of nitrous oxide that results in increased pressure and volume within the confined space. Nitrous oxide is lipid insoluble resulting in minimal uptake in fat, muscle, and solid organs.


Nitrous oxide has been shown to be effective in 85 percent of cases involving mild to moderate pain.5 The agent is a more potent anxiolytic than an analgesic. Anxiolysis is obtained by inducing a state of euphoria with a concurrent mild sedating effect. The analgesic effect is a result of an increase in the pain threshold. Combination therapy is often required due to its relatively weak analgesic effects, especially for painful procedures. For example, the infiltration of a local anesthetic agent for laceration repair is made more tolerable following the use of nitrous oxide.


Nitrous oxide used in an ambulatory care setting (e.g., Emergency Department, Dentist Office) is mixed with oxygen in a 50:50 mixture. Nitrous oxide becomes a more effective ...

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